The Cannabis Consortium Review of the Literature
The Tourette Association of America (TAA) understands and supports the need to improve the treatment of Tourette Syndrome (TS), Tic Disorders, and co-occurring conditions. The TAA has a track record of funding the development, evaluation and dissemination of effective treatments including pharmacological, behavioral and alternative therapies that reduce the burden of TS and Tic Disorders on our community. Based on currently available evidence, we provide here our current summary of the existing literature on the use of medical marijuana (cannabis) and cannabis-based medications for TS:
- A reduction in tics with medical marijuana and cannabis-based medicines has been reported in small studies, patient reports and anecdotal case reports. The neurobiological pathways targeted by medical marijuana and related therapies are deserving of more research and larger scale studies.
- There is the potential for adverse effects from medical marijuana and related plant-derived extracts that raise concern for treatment, especially in children and adolescents.
- The TAA supports removing regulatory barriers to allow for large-scale research studies of medical marijuana. There is currently insufficient scientific evidence to reach a definitive conclusion on the efficacy and safety of medical marijuana, cannabis-based medications, or related plant-derived extracts for the treatment of TS and other Tic Disorders.
What is medical marijuana?
Medical marijuana, also often called medical cannabis, refers to the use of marijuana obtained from an approved source and recommended by a healthcare provider to treat a medical condition. Medical marijuana is composed of the dried leaves, flowers, stems and seeds from the Cannabis genus plants, usually made from strains of Cannabis sativa or Cannabis Indica. The plants of Cannabis genus contain a large number of chemical compounds called phytocannabinoids, of which delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most abundant.
THC is the psychoactive component (the “high”) of the cannabis plant. CBD does not have psychoactive properties, but can have actions on the brain1–3. There are additionally over 100 phytocannabinoids and many other largely uncharacterized compounds in cannabis with the exact composition varying, depending on growing conditions, plant variety, and method of manufacturing/formulation4–8. In keeping with the regulations of a given state or country, medical marijuana can be consumed via inhalation, orally (alone or incorporated into edible food items), topically for designated medical conditions and in suppository form. Medical marijuana products are currently distributed by dispensaries in the U.S and, in some countries, by pharmacies. Regulation of medical marijuana is not uniform and depending on the state’s or country’s governmental regulations, medical marijuana and related products may contain contaminants13.
What are cannabis-based medicines?
Cannabis-based medicines are different from medical marijuana in that these medicines follow strict drug manufacturing regulations established by the US Food and Drug Administration (FDA) or equivalent regulatory bodies abroad. Cannabis-based medicines target the same pathways in the body as cannabis itself and include synthetic analogs of THC and CBD, standardized extracts of marijuana, or novel drugs that target the same pathways in the body as medical marijuana. These drugs have undergone regulated efficacy, toxicity and safety studies although not necessarily for Tourette Syndrome specifically. Once approved, these medications can be prescribed and monitored by a physician.
To date, the FDA has approved one cannabis-based medicine (for Epilepsy) but there are two cannabis-based medicines currently in development specifically for Tourette Syndrome: Therapix Biosciences has completed a Phase II clinical trial and is currently recruiting for Phase III. Abide Therapeutics (recently acquired by Lundbeck) has completed a Phase I trial. Early results from these studies are promising in terms of reduction in tics and/or premonitory urges, but more research is needed.
At the end of this report, we provide a table listing cannabis-based medicines, their approved indications, and their current status of clinical development.
Medical marijuana laws and regulation
At the present time medical marijuana is legal in 33 states and Washington D.C. and is specifically approved for the treatment of Tourette Syndrome in Arkansas, Illinois, Minnesota, Missouri, New Jersey and Ohio. CBD from hemp is now legal federally and readily available nationwide. Across states there is not necessarily uniformity in the testing and verification of medical marijuana and there is no set standard of efficacy in order for a state to approve medical marijuana for a specific medical condition. This variability in regulation complicates both research and treatment of Tourette Syndrome. First, marijuana and cannabis-derived natural products are not federally sanctioned despite being legal in the majority of the United States. In addition, marijuana in all of its forms continues to be classified by the federal government as a Schedule I drug*.
Academic/research institutions are subject to federal regulation and may be unable to approve research efforts on substances that may be legal locally but not federally. The layers of bureaucracy surrounding research of medical marijuana are a major challenge. The TAA supports a drug schedule re-evaluation for marijuana, thus removing regulatory barriers and allowing research to move forward more efficiently.
*Schedule I drugs are thought to have a high potential for abuse, have no currently accepted medical use in treatment, and have a lack of accepted safety. This is inconsistent with the authorization of marijuana use in 33 states and the District of Columbia for stated medical purposes, which the federal government has not interfered with. In addition, on September 27, 2018 the FDA granted the epilepsy medication Cannabidiol (Epidiolex®) classification in the less restrictive schedule V category, making this cannabis-derived drug for treatment resistant epilepsy an exception to the current standard.
The risks and benefits of marijuana for treating Tourette Syndrome
To date there have only been three FDA approved drugs for the treatment of Tourette Syndrome, but due to the potential side effects of these medications, they are not the first line of treatment for the symptoms of TS or Tic Disorders. More often, other better-tolerated medications that are FDA approved, albeit not for Tourette Syndrome, are used “off label”. The TAA recently conducted an impact survey, which found that 47% of adults and 44% of the parents of children with Tourette Syndrome do not feel that their symptoms are adequately controlled by existing medications45. It is in the best interest of the Tourette Syndrome community to explore the efficacy, potential benefits, and risks of any potential therapy, including medical marijuana.
There is a system within our bodies that responds to THC and other chemicals in cannabis called the “endocannabinoid system”14–16. This system modulates the release of most neurotransmitters in the brain including dopamine, glutamate, GABA, opioid peptides, and acetylcholine. When medical cannabis is used its chemicals modulate different receptor systems in the brain and these in turn affect neurotransmitter release. These chemicals also modulate the endocannabinoid system itself. In the basal ganglia region of the brain, a region important in Tourette, the chemicals in medical marijuana can interact with dopaminergic transmission, potentially controlling tics. Modulation of the dopaminergic system in other brain areas and of other transmitter systems might result in improving co-occurring disorders such as ADHD, OCD, and anxiety.
Recent small studies and patient reports suggest medical marijuana and cannabis-derived therapies have been helpful to individuals with Tourette Syndrome and Tic Disorders, but rigorous research studies with large patient numbers are lacking. Anecdotal case reports have long suggested that smoking marijuana or taking THC-containing products in various forms may improve tic symptoms18–27. These reports describe reductions of tics and pre-monitory urges, improvements in sleep, concentration and relaxation, and a reduction in depression, ADHD, OCD, and rage attacks. Standardized interviews of 64 consecutive TS patients seeking treatment in Germany reported that 82% of 17 TS patients who were marijuana users experienced a reduction or complete remission of tic symptoms28. A retrospective review of 19 adult Canadian patients who had used marijuana long-term in various forms (smoked, vaporized and/or edibles) and from various suppliers reported a 60% decrease in tic severity and improvement in co-occurring symptoms, though close to 60% reported adverse effects including sleepiness, dry mouth and appetite and decreased short term memory and concentration29. Since, the reported benefits are subjective descriptions from adults and teens, it is unclear to what extent these benefits are due to the psychoactive effects of marijuana such as reducing anxiety versus a direct impact on tics, or an impact on co-occurring conditions such as ADHD or OCD. It is also unclear whether these effects apply to a majority of TS patients. It should be noted that a recent review has concluded that there is limited evidence to suggest benefit of marijuana on Tourette Syndrome17.
There have been a few limited clinical trials of THC or THC-containing products in TS. One small double-blind, placebo-controlled crossover trial of 5-10mg per day of THC in 12 adults with TS demonstrated a significant reduction in self-reported measures of tic severity and global improvement with THC compared to placebo21. A 6-week, double-blind, placebo-controlled trial of 24 adults with TS also demonstrated a significant benefit of THC compared to placebo in some, but not all, of the outcomes assessed30. Seven subjects randomly assigned to THC who completed the study experienced significant reduction of their tic symptoms compared to placebo after the first 2 weeks of treatments that continued throughout the 6-week trial. These improvements did not persist when subjects discontinued THC.
While pure CBD has been approved for the treatment of certain forms of epilepsy, epilepsy is a neuromotor disorder with a different etiology than Tourette Syndrome. There are no case reports or scientific publications indicating the effectiveness of CBD alone or medical marijuana with high percentage of CBD and low percentage of THC in TS patients, although it has been suggested that adding CBD to THC may improve efficacy27. CBD itself can also cause adverse effects and CBD products sourced on-line may not have accurate labelling and in some cases may actually contain THC even if not labeled as such31.
It is important to note that the chemicals in marijuana, like any other chemical, medicine or drug may have adverse effects. The fact that marijuana is a natural product does not necessarily make it safe. Of specific concern is the potential risk of structurally and functionally altering brain development in children and adolescents37–42. Marijuana may affect the central nervous system (cognition, vision etc.) as well as other parts of the body. Depending on the medical conditions and genetic background of a person, the use of THC-containing products can lead to psychoactive effects including psychosis, euphoria and sometimes anxious reactions. Adverse effects of cannabis depend on the content and ratio of cannabinoids and other compounds in the cannabis, route of administration, drug-drug interactions, and patient-specific factors. The most common adverse effects of THC containing products are dizziness, sedation, “high” feeling, headache, red eyes, and increased appetite13,32,33. Epidemiological evidence and pre-clinical research in healthy subjects suggest that there may be an increased risk for psychosis in children and adolescents, and depression and cognitive impairment in children and adolescents33–36. Further, there is the potential risk of structurally and functionally altering the brain development of children/adolescents with cannabis treatment or exposure to THC37–42. Lastly, cannabis may interact or adversely affect the efficacy of other prescription medications an individual is taking. CBD has been shown to inhibit the degradation of drugs by the liver43,44. As such, it increases the potency of other medications. To guard against negative drug interactions, it is important that the physician knows all other medications the patient is taking before prescribing medical marijuana.
Research will be key to better understanding what future role medical marijuana can play in the treatment plan for individuals with TS.
A call for more research
The neurobiological pathways targeted by medical marijuana and cannabis-based medicines may turn out to be promising for understanding and alleviating tic symptoms and therefore deserve more research. A recent review of literature on cannabis and cannabinoid noted that “multiple barriers to conducting research on cannabis in the U.S. may explain the paucity of positive therapeutic benefits in the published literature to date.”17
Well-designed trials are ongoing internationally (ClinicalTrials.gov Identifier: NCT03087201,
NCT03247244, NCT03066193, NCT03058562, and Australian New Zealand Clinical Trials Identifier: ACTRN12618000545268) and the Tourette Association of America is supporting research on this topic (http://www.tourette.org/ grant-database/), but more research, especially on the potential adverse effects or risks for those with TS, needs to be done.
Given the potential impact of cannabis on the developing brain, evaluating the effects of medical cannabis products in adults with TS prior to conducting similar studies in youth is recommended. In addition to studying effects on tics, clinical studies investigating the effects on cognitive function, motor control, motivation, anxiety, depression, psychosis and the impact of routine use of cannabis on functional capacity including driving, school and work performance, and interpersonal relationships need to be performed in Tourette patients.
In order to make stronger recommendations for Tourette Syndrome regarding treatment with medical cannabis and cannabis-based medicines, a series of questions need to be addressed:
- Are medical cannabis and cannabis-based medicines indeed effective at reduction of tics in TS patients?
- If there is an effect on tic severity, is it a direct effect on tics or a secondary effect mediated by the reduction of anxiety or other co-occurring symptoms?
- If so, which specific compounds (including ratio of THC:CBD) and route of administration are most effective and best tolerated?
- If so, can medical cannabis or cannabis-based medicines be used as short or long-term treatment without loss of efficacy/tolerance?
- What are the specific characteristics of TS patients who are most likely to respond?
- Is there a risk of medical cannabis on the developing brain, and what is the short and long-term side effect profile in pediatric and adult patients? What is the functional impact on overall motor control, mood, anxiety, driving, school and work performance, and interpersonal relationships?
Further, randomized, large-scale, placebo-controlled human studies are needed to determine the efficacy and potential risks of cannabis and cannabis-based medicines, especially over time.
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Sharon Anavi-Goffer, PhD (University of Aberdeen) – United Kingdom
Michael Bloch, MD (Yale University) – United States
Cathy Budman, MD (Long Island Center for Tourette & Related Disorders) – United States
Barbara Coffey, MD MS (University of Miami) – United States
Keith Coffman, MD (Children’s Mercy Kansas City) – United States
Joohi Jimenez-Shahed, MD (Baylor College of Medicine) – United States
Irene Malaty, MD (University of Florida Center for Movement Disorders and Neurorestoration) – United States
Kirsten Muller-Vahl, MD (Hannover Medical School) – Germany
Paul Sandor, MD (University Health Network and University of Toronto, Toronto) – Canada
Diana Shineman, PhD (Tourette Association of America) – United States
John Walkup, MD (Lurie Children’s, Chicago) – United States
Abraham Weizman, MD (Director of Research Unit, Geha Mental Health Center) – Israel
TAA partners with many corporations including pharmaceutical companies. Abide Pharmaceuticals, mentioned in this report, is developing a synthetic monoacylglycerol lipase (MAGL) inhibitor for Tourette Syndrome, is a corporate sponsor of TAA. The TAA does not endorse any medicines or products.